2, 5-bis-(methyl-ethylenimino)-hydroquinones and process for preparation



2,5-BIS-(ME'lIHYL ETHYLENIMINO) HYDRO- QUINNONES AND PROCESS FOR PREPARA- TIO Adrian Marxer, Basel, Switzerland, assignor to Ciba Pharmaceutical Products Inc., Summit, N.-J.

No Drawing. Application January23, 1956 denial No. 560,880

Claims priority, application Switzerland January 2a, 1955 5 Claims. (31. 260-239) This invention relates to the new compound 2,5-bis- (methyl-ethylenimino)-hydroquinone of the formula OH H' i G-GHI HaC-C H OH its metal salts, and pharmaceutical preparations thereof.

The new compound is highly effective against Trichomonas and amoebae, for example, against Entamoeba histolytica.

It is known that aminoquinones are obtained by the reaction of quinones with amines. Aminohydroquinones have not yet been obtained in this manner (compare, for example, Martynoif and Tstatsas, Bulletin de la Socit Chimique de France, vol. 14, page 52 (1947), Cavallito, Soria and Hoppe, J. Am. Chem. Soc., vol. 72, page 2661 (1950) The present invention is based on the observation that in the reaction of quinone with C-methyl-ethylenimine bis (methyl ethylenimino) hydroquinone is obtained when certain reaction conditions are employed. Accordingly, the process of the invention is characterized in that para-quinone is reacted with C-methyl-ethylenimine, and the resulting 2,5-bis-(methyl-ethylenimino)-hydroquinone is isolated and/or any 2,5-bis-(methyl-ethylenimino)- para-quinone formed is treated with a reducing agent. More especially the reaction is conducted in a solvent, such as dioxane, ethyl alcohol, isopropyl alcohol or butyl alcohol, isopropyl ether or the like, and with a larger quantity of the C-methyl-ethylenimine than corresponds to the molecular ratio para-quinone:C-methyl-ethylenimine of 3:2, particularly in the molecular ratio 1:2 and especially from 1:25 to 1:4. The reaction is advantageously carried out in the absence of atmospheric oxygen, for example, in an atmosphere of nitrogen or hydrogen and at a raised temperature, for example -l00 C. The isolation of the product is carried out in known manner. Advantageously the quinone derivative formed in addition to the hydroquinone compound is extracted by means of a solvent.

According to the process of the invention a resulting mixture of 2,5-bis-(methyl-ethylenimino)-hydroquinone and 2,5-bis-(methyl-ethylenimino)-para-quinone can be culated quantity of cold acid, such as acetic acid. The re- 5 duction may also be carried out with other agentssuitable for the transformation of quinones to hydroquinqnes,

for-example with a dimetal hydride such as lithium-aluminurn hydride or sodium boron hydride, for example, in the presence of a solvent such as ether or dioxane. V

The resulting 2,5-bis-(methyl-ethylenimino)-hydroquinone may be converted into salts of metals. be dissolved in'an alkali hydroxide.

The present invention also comprises any modification of the process in which a compound obtainableas anintermediate product in the process, especially 2,5-bis-meth yl-ethylenimino)-para-quinone, is used as starting material and the remaining step or steps for example, the treatment with the reducing agent, are carried out. I

The 2,5 (bis methyl ethylenimino) hydroquinone or salts thereof, obtained according to the present invention can be used as medicaments in the treatment of lactose, starches, magnesium stearate, talc, vegetable oils,

benzyl alcohols, gums, polyalkylene glycols, petroleum jelly, cholesterol or other known carriers for medicaments. The pharmaceutical preparations may be made up, for example, in the form of tablets, dragees, salves, creams or in liquid form as solutions, suspensions or emulsions. If desired, they may be sterilized and/ or may contain auxiliary substances, such as preserving agents,

salts for regulating the osmotic pressure or butters. They may also contain other therapeutically valuable substances, for example, anti-bacterials.

The following examples illustrate the invention:

Example 1 43.2 grams of para-benzoquinone are dissolved in 350 cc. of dioxane. To the solution thereare added dropwise in the course of 15 minutes 57.0 grams of C-methyl-ethylenimine in cc. of dioxane, the internal temperature being maintained at 40-45 C. The whole is then stirred for a further 5 hours at 7 C. The resulting white precipitate is isolated by filtering with suction and washed with dioxane and alcohol. The micro-crystalline lamellae so obtained consist of analytically pure 2,5-bis-(methylethylenimino)-hydroquinone, which decomposes at 196 C. without melting.

Example 2 2.2 grams of 2,5-bis-(methyl-ethylenimino)para-quinone (obtained by reacting 3 mols of para-quinone with 2 mols of vC-rnethyl-ethylenimine in alcohol at 10 -20 C.)v

are suspended in cc. of absolute alcohol and agitated with hydrogen in the presence of 2 grams of Raney nickel. After a short time, 220 cc. of hydrogen are combined. The precipitated 2,5-bis-(methyl-ethylenimino)- hydroquinone is separated together with the nickel catalyst and agitated with 40 cc. of cold ln-caustic soda solution in a hydrogen atmosphere with good external cool,

ing, filtered to remove the nickel, and then immediately mixed with 20 cc. of cold Zn-acetic acid. The precipitated 2,5-bis (methyl ethylenimino) hydroquinone is washed with water andvalcohol, and dried. It is identical with the product obtained according to Example 1.

2,833,760; Patented May 6, 1958.

Thus it may 7 ethyleniminoypara-quinone'in a small quantity of water 1 added 4 ee. 9f ,ln-eaustic ,soda solution isimulta'ne' the quantity of; asolution of,8.,4- grams of sodithionite in '30 cc. of water 1 necessary to produce {a dear solution Thereact ion-m ass -is immediatelyeneluing preqipitate filtered off with suetionafterashott while, ,theqwashed and-d -ied. It consists of 2,5-bis-(methylethylenimino) -hyd1 oquinone and is identical with the sub- Example 4 c uiiiohelobtaihed according toiExample l, 2 or 3 are distsfolyed in 20 ca; of: 0Q ln-caustic soda solution with the 1 XC111S1OH or atmospheric oxygen and sealed immediately in,anevacuatedjlass ampoulej, Infthisv'vay there is 0b 1; ff'tziinedan' aqueous solution of thefdisodiuin salt of 2,5-bisi--(fiietihil-ethylenimino -'hydroquinone.

fLfI-A fcompoundof the group consisting of 2,5 -bis f (methyl-ethylenimino)-hydroquinone andthe alkali metal Salts thereof.

1t: zed with about 9,cc, of Zn-acetic acid and the iesult 1 stance obtained accordingt o Example 101' 2. 1 Y

1 1 25b 11111111 111 1; of '2,'5-bis(methil-ethylenimino)-hydro-' 2. A process which comprises reacting para-quinone with C methyl ethylenimine "in 'a molecular ratio of'from about 1:25 to about 1:4 at a temperature of from about 40 C. to about 100 C., and isolating the resulting 2,5- 5 bis-(methyl-ethylenimino)-hydroquinone.

3. Aprocess accotding to claim 2 wherein the reaction is agree- 1 a; undet anaerobieeonditions' 1 4. '2,5 bis-'(methyl-ethylenimino)-hydi'oquinone.

5. The sodium salt of the compound of claim 4.

Retel -antes Cited in the file ofthis patent UNITED STATES PATENTS 2,770,617 Marxer Nov. 13, 1956 15 FOREIGN PATENTS 1,118,425 France Mar. 19, 1956 OTHER REFERENCES 20 Domagk at all; =Ch'em. Abstracts, vol.-48, call 11658 Pratesi: Chem; 'A'bsL, vol. 31, cols. 1024-5 (1937). Bu Lock et a1.: J. Chem. 'Soc., vol. 1951, pp. 703-12. 

1. A COMPOUND OF THE GROUP CONSISTING OF 2,5-BIS(METHYL-ETHYLENIMINO)-HYDROQUINONE AND THE ALKALI METAL SALTS THEREOF. 